The present invention relates to a process for the manufacture of coated articles wherein the coating comprises a polymer having desirable characteristics regarding adherence to the substrate, durability, hydrophilicity, wettability, biocompatibility and permeability. More particular, the present invention relates to a process for the modification of the surface of an article, such as a biomedical material or article, especially a contact lens including an extended-wear contact lens wherein the articles are at least partly coated with a polymer having a xe2x80x9cbottle-brushxe2x80x9d type structure composed of tethered xe2x80x9chairyxe2x80x9d chains.
A variety of different types of processes for preparing polymeric coatings on a substrate have been disclosed in the prior art. For example, U.S. Pat. No. 5,527,925 describes functionalized photoinitiators and also organic substrates such as contact lenses containing said photoinitiators covalently bound to their surface. In one embodiment of said disclosure, the so modified surface of the contact lens is further coated with a photopolymerizable ethylenically unsaturated monomer which is then polymerized by irradiation thus forming a novel substrate surface. With this method, however, it is not always possible to obtain the desired coating characteristics, for example wettability characteristics which are necessary for the surface of biomedical devices including contact lenses. In particular, the ability of the known materials to attract and stabilize a continuous layer of an aqueous solution, e.g. human body fluids such as tears or mucus layers, for a prolonged period of time which is an important feature for many biomedical applications is not yet satisfactory.
Surprisingly, it now has been found that articles, particularly biomedical devices such as contact lenses, with an improved wettability, water-retention ability and biocompatibility are obtained by first of all providing the article surface with a brush-type primary polymer coating comprising polymerization initiator radicals; and then grafting one or more different ethylenically unsaturated hydrophilic monomers onto the initiator-modified polymer chains that make up the brush structure.
The present invention therefore in one aspect relates to a process for coating a material surface, comprising the steps of:
(a) providing the material surface with polymer brushes comprising polymerization initiator radicals; and
(b) graft polymerizing one or more different ethylenically unsaturated hydrophilic monomers or macromonomers onto the polymerization initiator-modified polymer brushes.
Examples of materials that may be coated according to the process of the invention are quartz, ceramics, glasses, silicate minerals, silica gels, metals, metal oxides, carbon materials such as graphite or glassy carbon, natural or synthetic organic polymers, or laminates, composites or blends of said materials, in particular natural or synthetic organic polymers which are known in large number. Some examples of polymers are polyaddition and polycondensation polymers (polyurethanes, epoxy resins, polyethers, polyesters, polyamides and polyimides); vinyl polymers (polyacrylates, polymethacrylates, polystyrene, polyethylene and halogenated derivatives thereof, polyvinyl acetate and polyacrylonitrile); elastomers (silicones, polybutadiene and polyisoprene); or modified or unmodified biopolymers (collagen, cellulose, chitosan and the like).
A preferred group of materials to be coated are those being conventionally used for the manufacture of biomedical devices, e.g. contact lenses, in particular contact lenses for extended wear, which are not hydrophilic per se. Such materials are known to the skilled artisan and may comprise for example polysiloxanes, perfluoropolyethers, fluorinated poly(meth)acrylates or equivalent fluorinated polymers derived e.g. from other polymerizable carboxylic acids, polyalkyl (meth)acrylates or equivalent alkylester polymers derived from other polymerizable carboxylic acids, or fluorinated polyolefines, such as fluorinated ethylene propylene, or tetrafluoroethylene, preferably in combination with specific dioxols, such as perfluoro-2,2-dimethyl-1,3-dioxol. Examples of suitable bulk materials are e.g. Lotrafilcon A, Neofocon, Pasifocon, Telefocon, Silafocon, Fluorsilfocon, Paflufocon, Silafocon, Elastofilcon, Fluorofocon or Teflon AF materials, such as Teflon AF 1600 or Teflon AF 2400 which are copolymers of about 63 to 73 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 37 to 27 mol % of tetrafluoroethylene, or of about 80 to 90 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % of tetrafluoroethylene.
Another preferred group of materials to be coated are those being conventionally used for the manufacture of biomedical devices, e.g. contact lenses, which are hydrophilic per se, since reactive groups, e.g. carboxy, carbamoyl, sulfate, sulfonate, phosphate, amine, ammonium or hydroxy groups, are inherently present in the material and therefore also at the surface of a biomedical device manufactured therefrom. Such materials are known to the skilled artisan and comprise for example polyhydroxyethyl acrylate, polyhydroxyethyl methacrylate (HEMA), polyvinyl pyrrolidone (PVP), polyacrylic acid, polymethacrylic acid, polyacrylamide, polydimethylacrylamide (DMA), polyvinyl alcohol or copolymers for example from two or more monomers from the group hydroxyethyl acrylate, hydroxyethyl methacrylate, N-vinyl pyrrolidone, acrylic acid, methacrylic acid, acrylamide, dimethyl acrylamide, vinyl alcohol and the like. Typical examples are e.g. Polymacon, Tefilcon, Methafilcon, Deltafilcon, Bufilcon, Phemfilcon, Ocufilcon, Focofilcon, Etafilcon, Hefilcon, Vifilcon, Tetrafilcon, Perfilcon, Droxifilcon, Dimefilcon, Isofilcon, Mafilcon, Nelfilcon or Atlafilcon.
Still another group of preferred materials to be coated are amphiphilic segmented copolymers comprising at least one hydrophobic segment and at least one hydrophilic segment which are linked through a bond or a bridge member. Examples are silicone hydrogels, for example those disclosed in PCT applications WO 96/31792 and WO 97/49740 which are herewith incorporated by reference.
The material to be coated may also be any blood-contacting material conventionally used for the manufacture of renal dialysis membranes, blood storage bags, pacemaker leads or vascular grafts. For example, the material to be modified on its surface may be a polyurethane, polydimethylsiloxane, polytetrafluoroethylene, polyvinylchloride, Dacron(trademark) or a composite made therefrom.
Moreover, the material to be coated may also be an inorganic or metallic base material with or without suitable reactive groups, e.g. ceramic, quartz, or metals, such as silicon or gold, or other polymeric or non-polymeric substrates. E.g. for implantable biomedical applications, ceramics or carbohydrate containing materials such as polysaccharides are very useful. In addition, e.g. for biosensor purposes, dextran coated base materials are expected to reduce nonspecific binding effects if the structure of the coating is well controlled. Biosensors may require polysaccharides on gold, quartz, or other non-polymeric substrates.
The form of the material to be coated may vary within wide limits. Examples are particles, granules, capsules, fibres, tubes, films or membranes, preferably moldings of all kinds such as ophthalmic moldings, in particular contact lenses.
The polymer brushes according to step (a) of the process of the invention may be provided, for example, by
(a1) covalently binding polymerization initiator radicals to the surface;
(a2) graft polymerizing a vinyl monomer carrying a reactive group onto the initiator-modified material surface and thereby providing the surface with polymer brushes comprising reactive groups; and
(a3) reacting the reactive groups of the polymer brushes with a polymerization initiator having a functional group that is coreactive with the reactive groups of the polymer brushes.
According to this embodiment of the invention, in the initial state, the material to be coated carries initiator moieties for radical polymerization covalently bound to its surface. According to a preferred embodiment of the invention, the initiator moieties are covalently bound to the surface of the material to be modified on its surface via reaction of a functional group of the material surface with a reactive group of the initiator molecule.
Suitable functional groups may be inherently (a priori) present at the surface of the material to be modified on its surface. If substrates contain too few or no reactive groups, the material surface can be modified by methods known per se, for example plasma chemical methods (see, for example, WO 94/06485), or conventional functionalization with groups such as xe2x80x94OH, xe2x80x94NH2 or xe2x80x94CO2H produced. Suitable functional groups may be selected from a wide variety of groups well known to the skilled artisan. Typical examples are e.g. hydroxy groups, amino groups, carboxy groups, carbonyl groups, aldehyde groups, sulfonic acid groups, sulfonyl chloride groups, isocyanato groups, carboxy anhydride groups, lactone groups, azlactone groups, epoxy groups and groups being replaceable by amino or hydroxy groups, such as halo groups, or mixtures thereof. Amino groups and hydroxy groups are preferred.
Polymerization initiators bound on the surface of the material to be coated are typically those that are initiating a radical polymerization of ethylenically unsaturated compounds. The radical polymerization may be induced thermally, or preferably by irradiation.
Suitable thermal polymerization initiators are known to the skilled artisan and comprise for example peroxides, hydroperoxides, azo-bis(alkyl- or cycloalkylnitriles), persulfates, percarbonates or mixtures thereof. Examples are benzoylperoxide, tert.-butyl peroxide, di-tert.-butyl-diperoxyphthalate, tert.-butyl hydroperoxide, azo-bis(isobutyronitrile), 1,1xe2x80x2-azo-bis (1-cyclohexanecarbonitrile), 2,2xe2x80x2-azo-bis(2,4-dimethylvaleronitrile), 4,4xe2x80x2-azo-bis(4-cyano-valeric acid, 4,4xe2x80x2-azo-bis(4-cyano-n-pentanol) and the like. The thermal initiators may be linked to the surface of the bulk material by methods known per se, for example as disclosed in EP-A-037851 1. Initiators for the thermal polymerization are particularly functional initiators having an initiator part such as a peroxide, hydroperoxide, persulfate or azo group and in addition a functional group that is coreactive with functional groups of the substrate, particularly with xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, epoxy, carboxyanhydride, alkylamino,xe2x80x94COOH or isocyanato groups. Suitable functional groups that are coreactive with the surface of the bulk material are for example a carboxy, hydroxy, epoxy or isocyanato group. A particular preferred group of thermal initiators are azo-bis(C2-C12-alkane carboxylic acids) or azo-bis(C2-C12-alkanols) wherein the alkane moiety in each case may be further substituted, for example, by cyano.
Initiators for the radiation-induced polymerization are particularly functional photoinitiators having a photoinitiator part and in addition a functional group that is coreactive with functional groups of the substrate, particularly with xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, epoxy, carboxanhydride, alkylamino,xe2x80x94COOH or isocyanato groups. The photoinitiator part may belong to different types, for example to the thioxanthone type and preferably to the benzoin type. Suitable functional groups that are coreactive with the surface of the bulk material are for example a carboxy, hydroxy, epoxy or isocyanato group.
Preferred polymerization initiators for use in the present invention are the photoinitiators of formulae (I) and (Ia) as disclosed in U.S. Pat. No. 5,527,925, those of the formula (I) as disclosed in PCT application WO 96/20919, or those of formulae II and III including formulae IIa-IIy and IIIg as disclosed in EP-A-0281941, particularly formulae IIb, IIi, IIm, IIn, IIp, IIr, IIs, IIx and IlIg therein. The respective portion of said three documents including the definitions and preferences given for the variables in said formulae are herewith included by reference.
The polymerization initiator moieties are preferably derived from a functional photoinitiator of the formula 
wherein Z is bivalent xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94 or xe2x80x94NR12xe2x80x94; Z1 is xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94(O)Cxe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94; R3 is H, C1-C12-alkyl, C1-C12-alkoxy or Nxe2x80x94C1-C12-alkylamino; R4 and R5 are each independently of the other H, linear or branched C1-C8-alkyl, C1-C8-hydroxyalkyl or C6-C10-aryl, or the groups R4xe2x80x94(O)b1xe2x80x94 and R4xe2x80x94(O)b2xe2x80x94 together are xe2x80x94(CH2)cxe2x80x94 wherein c is an integer from 3 to 5, or the groups R4xe2x80x94(O)b1xe2x80x94, R4xe2x80x94(O)b2xe2x80x94 and R5xe2x80x94(O1)b3xe2x80x94 together are a radical of the formula 
R2 is a direct bond or linear or branched C1-C8-alkylene that is unsubstituted or substituted by xe2x80x94OH and/or is uninterrupted or interrupted by one or more groups xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94 or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94; R1 is branched C3-C18-alkylene, unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted C6-C10-arylene, or unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted C7-C18-aralkylene, unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted C3-C8-cycloalkylene, unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted C3-C8-cyclo-alkylene-CyH2yxe2x80x94 or unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted xe2x80x94CyH2y-(C3-C8-cycloalkylene)-CyH2yxe2x80x94 wherein y is an integer from 1 to 6; R6 independently has the same definitions as R1 or is linear C3-C18-alkylene; R12 is linear or branched C1-C6-alkyl; T is bivalent xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, C1-C8-alkylene or 
Z2 is a direct bond or xe2x80x94Oxe2x80x94(CH2)dxe2x80x94 wherein d is an integer from 1 to 6 and the terminal CH2 group of which is linked to the adjacent T in formula (10c); R8 is linear or branched C1-C8-alkyl, C2-C8-alkenyl or C6-C10-aryl-C1-C8-alkyl; R9 independently of R8 has the same definitions as R8 or is C6-C10-aryl, or R8 and R9 together are xe2x80x94(CH2)exe2x80x94 wherein e is an integer from 2 to 6; R10 and R11 are each independently of the other linear or branched C1-C8-alkyl that may be substituted by C1-C4-alkoxy, or C6-C10-aryl-C1-C8-alkyl or C2-C8-alkenyl; or R10 and R11 together are xe2x80x94(CH2)f1xe2x80x94Z3xe2x80x94(CH2)f2xe2x80x94 wherein Z3 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR7xe2x80x94, and R7 is H or C1-C8-alkyl and f1 and f2 are each independently of the other an integer from 2 to 4; R13 and R13xe2x80x2 are each independently of the other H, C1-C8-alkyl, C3-C8-cycloalkyl, benzyl or phenyl; and a, a1, b1, b2 and b3 are each independently of the other 0 or 1; subject to the provisos that b1 and b2 are each 0 when R15 is H; that the total of (b1+b2+b3) is not exceeding 2; and that a is 0 when R12 is a direct bond.
A preferred sub-group of compounds of formula (1a) or (1b) comprises those wherein, b1 and b2 are each 0; Z and Z1 are each bivalent xe2x80x94Oxe2x80x94; b3 is 0 or 1; R4 is C1-C4-alkyl or phenyl, or both groups R4 together are tetramethylene or pentamethylene; R5 is C1-C4-alkyl or H, R3 is hydrogen; a and al are each independently 0 or 1; R2 is linear or branched C2-C4-alkylene, or is a direct bond, in which case a is 0; R1 is branched C5-C10-alkylene, phenylene or phenylene substituted by from 1 to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3 methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3 methyl groups, cyclohexyl-CyH2yxe2x80x94 or xe2x80x94CyH2y-cyclohexyl-CyH2yxe2x80x94 or cyclohexyl-CyH2yxe2x80x94 or xe2x80x94CyH2y-cyclohexyl-CyH2y-substituted by from 1 to 3 methyl groups; and y is 1 or 2.
An especially preferred sub-group of compounds of formula (1a) or (1b) comprises those wherein, b1 and b2 are each 0, Z and Z1 are each bivalent xe2x80x94Oxe2x80x94, b3 is 0 or 1; R4 is methyl or phenyl, or both groups R4 together are pentamethylene; R5 is methyl or H; R3 is hydrogen; a is 1 and R2 is ethylene, or a is 0 and R2 is a direct bond; a1 is 0 or 1; and R1 is branched C6-C10-alkylene, phenylene or phenylene substituted by from 1 to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3 methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3 methyl groups, cyclohexyl-CH2xe2x80x94 or cyclohexyl-CH2-substituted by from 1 to 3 methyl groups.
A preferred sub-group of compounds of formula (1c) comprises those wherein T is bivalent xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94(CH2)yxe2x80x94 wherein y is an integer from 1 to 6; Z2 is a direct bond or xe2x80x94Oxe2x80x94(CH2)yxe2x80x94 wherein y is an integer from 1 to 6 and the terminal CH2 group of which is linked to the adjacent T in formula (10c); R3 is H, C1-C12-alkyl or C1-C12-alkoxy; R8 is linear C1-C8-alkyl, C2-C8-alkenyl or C6-C10-aryl-C1-C8-alkyl; R9 independently of R8 has the same definitions as R8 or is C6-C10-aryl, or R8 and R9 together are xe2x80x94(CH2)exe2x80x94 wherein e is an integer from 2 to 6; R10 and R11 are each independently of the other linear or branched C1-C8-alkyl that may be substituted by C1-C4-alkoxy, or C6-C10-aryl-C1-C8-alkyl or C2-C8-alkenyl; or R10 and R11 together are xe2x80x94(CH2)f1xe2x80x94Z3xe2x80x94(CH2)f2xe2x80x94 wherein Z3 is a direct bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NR7xe2x80x94, and R7 is H or C1-C8-alkyl and f1 and f2 are each independently of the other an integer from 2 to 4; and R6 is branched C6-C10-alkylene, phenylene or phenylene substituted by from 1 to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3 methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3 methyl groups, cyclohexylene-CH2xe2x80x94 or cyclohexylene-CH2-substituted by from 1 to 3 methyl groups.
An especially preferred sub-group of compounds of formula (1c) comprises those wherein T is bivalent xe2x80x94Oxe2x80x94; Z2 is xe2x80x94Oxe2x80x94(CH2)yxe2x80x94 wherein y is an integer from 1 to 4 and the terminal CH2 group of which is linked to the adjacent T in formula (10c); R3 is H; R8 is methyl, allyl, tolylmethyl or benzyl, R9 is methyl, ethyl, benzyl or phenyl, or R8 and R9 together are pentamethylene, R10 and R11 are each independently of the other C1-C4-alkyl or R10 and R11 together are xe2x80x94CH2CH2OCH2CH2xe2x80x94, and R6 is branched C6-C10-alkylene, phenylene or phenylene substituted by from 1 to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3 methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3 methyl groups, cyclohexylene-CH2xe2x80x94 or cyclohexylene-CH2-substituted by from 1 to 3 methyl groups.
Some examples of especially preferred functional photoinitiators are the compounds of formulae 
wherein R22 is a radical 
In a preferred embodiment of the invention, the covalent binding between the inorganic or preferably material surface and the photoinitiator occurs via reaction of a hydroxy, amino, alkylamino, thiol or carboxy group, particularly of a hydroxy or amino group, of the substrate surface with an isocyanato group of the photoinitiator, for example using a photoinitiator of the above formula (1b), (1c), (11a), (11b) or (11c). Suitable methods for this are known, for example, from the above-mentioned documents. The reaction may be carried out, for example, at elevated temperature, for example from 0xc2x0 to 100xc2x0 C. and preferably at room temperature, and optionally in the presence of a catalyst. After the reaction, excess compounds can be removed, for example, with solvents.
According to a preferred embodiment of the invention the material to be coated is an organic polymer containing H-active I groups, in particular xe2x80x94OH, xe2x80x94NH2 and/or xe2x80x94NHxe2x80x94, on the surface that are coreactive with isocyanato groups, in some or all of them an H-atom having been substituted by a radical of formula 
wherein for the variables R1-R11, T, Z, Z1, Z2, a, b1, b2 and b3 the above-given meanings and preferences apply.
According to another preferred embodiment of the invention, the covalent binding between the inorganic or preferably organic substrate and the photoinitiator occurs via reaction of a epoxy, carboxanhydride, lactone, aziactone or preferably isocyanato group of the substrate surface with a hydroxy, amino, alkylamino, thiol or carboxy group, particularly with a carboxy, hydroxy or amino group, of the photoinitiator, for example using a photoinitiator of the above formula (1a). This may be carried out, for example, by first reacting an above-mentioned bulk material containing H-active groups on the surface, in particular xe2x80x94OH, xe2x80x94NH2 and/or xe2x80x94NH, selectively with one isocyanato group of a diisocyanate of formula OCNxe2x80x94R1xe2x80x94NCO, wherein R1 has the above-given meanings, and then reacting the modified bulk material with a photoinitiator of the above-mentioned formula (1a).
Suitable reactive groups of the vinyl monomer according to step (a2) are, for example, a hydroxy, amino, carboxy, carboxylic acid ester, carboxylic acid anhydride, epoxy, lactone, azlactone or isocyanato group. One group of preferred reactive groups comprises carboxy, carboxylic acid anhydride, azlactone or isocyanato, in particular isocyanato. Another group of preferred reactive groups comprises amino or in particular hydroxy.
The vinyl monomer that is grafted onto the initiator-modified surface according to step (a2) is, for example, an ethylenically unsaturated compound having from 2 to 18 C-atoms and preferably from 2 to 10 C-atoms, which is substituted by a reactive group, wherein the above-given meanings and preferences apply.
Suitable vinyl monomers having a reactive group are, for example, a compound of formula 
wherein R14 is hydrogen, unsubstituted or hydroxy-substituted C1-C6-alkyl or phenyl,
R15, and R16 are each independently of the other hydrogen, C1-C4-alkyl, phenyl, carboxy or halogen,
R17 is hydrogen, C1-C4-alkyl or halogen,
R18 and R18xe2x80x2 are each an ethylenically unsaturated radical having from 2 to 6 C-atoms, or
R18 and R18xe2x80x2 together form a bivalent radical xe2x80x94C(R15)xe2x95x90C(R17)xe2x80x94 wherein R15 and R17 are as defined above, and
(Alk*) is C1-C6-alkylene, and (Alk**) is C2-C12-alkylene.
The following preferences apply to the variables contained in formulae (2a)-(2e):
R14 is preferably hydrogen or hydroxy-C1-C4-alkyl, in particular hydrogen or xcex2-hydroxyethyl.
One of the variables R15 and R16 is preferably hydrogen and the other one is hydrogen, methyl or carboxy. Most preferably R15 and R16 are each hydrogen.
R17 is preferably hydrogen or methyl.
R18 and R18xe2x80x2 are preferably each vinyl or 1-methylvinyl, or R18 and R18xe2x80x2 together form a radical xe2x80x94C(R15)xe2x95x90C(R17)xe2x80x94 wherein R15 and R17 are each independently hydrogen or methyl.
(Alk*) is preferably methylene, ethylene or 1,1-dimethyl-methylene, in particular a radical xe2x80x94CH2xe2x80x94 or xe2x80x94C(CH3)2xe2x80x94.
(Alk**) is preferably C2-C4-alkylene and in particular 1,2-ethylene.
Particularly preferred vinyl monomers having a reactive group are 2-isocyanatoethylmeth-acrylate (IEM), 2-vinyl-azlactone, 2-vinyl-4,4-dimethyl-azlactone, acrylic acid, methacrylic acid, acrylic anhydride, maleic acid anhydride, 2-hydroxyethylacrylate (HEA), 2-hydroxymethacrylate (HEMA), glycidylacrylate or glycidylmethacrylat.
Throughout the application terms such as carboxy, carboxylic acid, xe2x80x94COOH, sulfo, xe2x80x94SO3H, amino, xe2x80x94NH2 and the like always include the free acid or amine as well as a suitable salt thereof, for example a biomedically or in particular occularly acceptable salt thereof such as, for example, a sodium, potassium, ammonium salt or the like (of an acid), or a hydrohalide such a hydrochloride (of an amine).
The vinyl monomer having a reactive group may be grafted as such or in admixture with a suitable vinyl comonomer, preferably a hydrophilic vinyl comonomer, onto the material surface.
The expression xe2x80x9chydrophilic vinyl comonomerxe2x80x9d is understood to mean a monomer that typically produces as homopolymer a polymer that is water-soluble or capable of absorbing at least 10% by weight water.
The proportion of vinyl comonomers, if used, is preferably from 0.1 to 3 units per vinyl monomer having a reactive group, especially from 0.25 to 3 units of vinyl comonomer per vinyl monomer having a reactive group and most preferably from 0.5 to 2 units per vinyl monomer having a reactive group.
Suitable hydrophilic vinyl comonomers include, without the following being an exhaustive list, C1-C2-alkyl acrylates and methacrylates, acrylamide, methacrylamide, N-mono- or N,N-di-C1-C2-alkylacrylamide and -methacrylamide, ethoxylated acrylates and methacrylates, sodium ethylenesulfonate, sodium styrenesulfonate, 2-acrylamido-2-methylpropanesulfonic acid, N-vinylpyrrole, N-vinylsuccinimide, five- to seven-membered N-vinyl lactams, 2- or 4-vinylpyridine, amino- (the term xe2x80x9caminoxe2x80x9d also including quatemary ammonium), mono-C1-C2-alkylamino- or di-C1-C2-alkylamino-C1-C2-alkyl acrylates and methacrylates, allyl alcohol and the like. Preferred are acrylamide, N,N-di-C1-C2-alkyl(meth)acrylamides such as N,N-dimethyl acrylamide or five- to seven-membered N-vinyl lactams such as N-vinylpyrrolidone.
In one embodiment of the invention the vinyl monomer having a reactive group is grafted to the initiator-modified material surface in the absence of a vinyl comonomer.
The vinyl monomer having a reactive group, optionally in admixture with a vinyl comonomer, may be applied to the initiator-modified material surface and polymerized there according to processes known per se. For example, the material is immersed in a solution of the vinyl monomer(s), or a layer of vinyl monomer(s) is first of all deposited on the modified material surface, for example, by dipping, spraying, spreading, knife coating, pouring, rolling, spin coating or vacuum vapor deposition. Suitable solvents, if used in the polymerization process, are, for example, water, C1-C4-alcanols such as methanol or ethanol, glycols such as ethylene glycol or dipolar aprotic solvents such as, for example, acetonitrile, N,N-dimethyl formamide (DMF), N-methyl pyrrolidone (NMP), dimethyl sulfoxide (DMSO), N,N-dimethyl acetamide or acetone. The polymerization of the vinyl monomer(s) on the material surface then may be initiated , for example, thermally by the action of heat or preferably by irradiation, particularly by UV radiation. Suitable light sources for the irradiation are known to the artisan and comprise for example mercury lamps, high pressure mercury lamps, xenon lamps, carbon arc lamps or sunlight. The time period of irradiation may depend, for example, on the desired properties of the resulting composite material but is usually in the range of up to 30 minutes, preferably from 10 secondes to 10 minutes, and particularly preferably from 0.5 to 5 minutes. It is advantageous to carry out the irradiation in an atmosphere of inert gas. After the polymerization, any non-covalently bound monomers, oligomers or polymers formed can be removed, for example by treatment with suitable solvents.
In case of a thermally initiated polymerization of the vinyl monomer(s) on the material surface said polymerization may be carried out, for example, at elevated temperature, for example at a temperature of from 35 to 100xc2x0 C. and preferably 40 to 80xc2x0 C., for a time period of, for example, from 10 minutes to 48 hours and preferably 30 minutes to 36 hours in the absence or presence of one of the above-mentioned solvents. It is advantageous to carry out the thermally initiated polymerization in an atmosphere of inert gas.
By means of the polymerization step (a2), the vinyl monomer(s) may be grafted to the bulk material surface with formation of a primary coating comprising a plurality of polymer chains bound to the surface which form a so-called brush-type structure. Each polymer chain of said brush-type structure contains reactive groups at regular intervals (if the vinyl monomer comprising the reactive group is used without a vinyl comonomer) or statistically distributed (if the vinyl monomer comprising the reactive group is used in combination with a vinyl comonomer). The reactive groups that are present in the polymer chains are those mentioned before in the description of the vinyl monomers comprising a reactive group.
The reactive polymerization initiator of step (a3) is, for example, one of the thermal initiators or photoinitiators as mentioned in step (a1) wherein the above-given meanings and preferences apply. Preferred polymerization initiators of step (a3) are, in case of thermal initiators, azo-bis(C2-C12-alkanols) which are substituted by cyano, or are, in case of photoinitiators, compounds of the above formula (1a) wherein the above given meanings and preferences apply.
The reactions of the reactive groups of the polymer brushes obtained according to step (a2) with the polymerization initiator having co-reactive groups in step (a3) are well-known in the art and may be carried out as desribed in textbooks of organic chemistry. For example, in case that the primary coating is derived from a vinyl monomer of formula (2e) or the like, the reaction of its isocyanato groups with a compound of formula (1a) may be carried out in an inert organic solvent such as acetonitrile, an optionally halogenated hydrocarbon, for example petroleum ether, methylcyclohexane, toluene, chloroform, methylene chloride and the like, or an ether, for example diethyl ether, tetrahydrofurane, dioxane, or a more polar solvent such as DMSO, DMA, N-methylpyrrolidone or even a lower alcohol or water, at a temperature of from 0 to 100xc2x0 C., preferably from 0 to 50xc2x0 C. and particularly preferably at room temperature, optionally in the presence of a catalyst, for example a tertiary amine such as triethylamine or tri-n-butylamine, 1,4-diazabicyclooctane, or a tin compound such as dibutyltin dilaurate or tin dioctanoate. In addition, the reaction of the isocyanato groups of the polymer brushes with a compound of formula (1a) wherein HZxe2x80x94 is an amino group and a1 is 0, also may be carried out in an aqueous solution in the absence of a catalyst. It is advantageous to carry out the above reactions under an inert atmosphere, for example under a nitrogen or argon atmosphere.
In case that the polymer brushes are derived from a vinyl monomer of formula (2d) or the like, the reaction of the azlactone groups with a compound of formula (1a) wherein HZxe2x80x94 is an amino or hydroxy group and a1 is 0, may be carried out at room temperature or at elevated temperature, for example at about 20 to 75xc2x0 C., in water, in a suitable organic solvent or mixtures thereof, for example in an aqueous medium or in an aprotic polar solvent such as DMF, DMSO, dioxane, acetonitrile and the like.
In case that the polymer brushes are derived from a vinyl monomer of formula (2c) or the like, the reaction of the epoxy groups with a compound of formula (1a) wherein HZxe2x80x94 is an amino group and a1 is 0, may be carried out, for example, at room temperature or at elevated temperature, for example at about 20 to 100xc2x0 C., in water, in a suitable organic solvent or in mixtures thereof.
In case that the polymer brushes are derived from a vinyl monomer of formula (2c) or the like, the reaction of the epoxy groups with a compound of formula (1a) wherein HZxe2x80x94 is an hydroxy group and al is 0, may be carried out, for example, at room temperature or at elevated temperature, for example at about 20 to 100xc2x0 C., in an aprotic medium using a base catalyst, for example Al(Oxe2x80x94C1-C6-alkyl)3 or Ti(Oxe2x80x94C1-C6-alkyl)3.
In case that the polymer brushes are derived from a vinyl monomer of formula (2b) or the like, the reaction of the carboxy anhydride with a compound of formula (1a) wherein X is an amino or hydroxy group and a1 is 0, may be carried out as described in organic textbooks, for example in an aprotic solvent, for example one of the above-mentioned aprotic solvents, at a temperature from room temperature to about 100xc2x0 C.
In case that the polymer brushes are derived from a vinyl monomer of formula (2a) or the like, the reaction of its carboxy or hydroxy groups with a compound of formula (1a), wherein HZxe2x80x94[C(O)a1]xe2x80x94 is amino, hydroxy or carboxy, may be carried out under the conditions that are customary for ester or amide formation,
In case that the primary coating is derived from a vinyl monomer of formula (2a) or the like, the reaction of its carboxy groups with a compound of formula (1a), wherein HZxe2x80x94[C(O)a1]xe2x80x94 is amino or hydroxy, or the reaction of its amino or hydroxy groups with a compound of formula (1a), wherein HZxe2x80x94[C(O)a1]xe2x80x94 is carboxy, may be carried out under the conditions that are customary for ester or amide formation, for example in an aprotic medium at a temperature from about room temperature to about 100xc2x0 C. In case of a carboxy containing compound of formula (2a) it is preferred to carry out the esterification or amidation reaction in the presence of an activating agent, for example N-ethyl-Nxe2x80x2-(3-dimethyl aminopropyl)-carbodiimide (EDC), N-hydroxy succinimide (NHS) or N,Nxe2x80x2-dicyclohexyl carbodiimide (DCC).
According to a further embodiment of the invention, the polymer brushes according to step
(a) of the process may be provided by
(a1) covalently binding polymerization initiator radicals to the surface; and
(a2xe2x80x2) graft polymerizing an ethylenically unsaturated polymerization initiator onto the initiator-modified material surface, wherein said ethylenically unsaturated polymerization initiator is a photoinitiator in case of a thermal initiator in step (a1), or is a thermal initiator in case of a photoinitiator in step (a1).
According to this embodiment of the invention, the polymerization initiator of step (a1) is preferably a thermal polymerization initiator, in particular one of the thermal polymerization initiators mentioned before; and the ethylenically unsaturated polymerization initiator of step (a2xe2x80x2) is a photoinitiator.
A group of suitable photoinitiators according to step (a2xe2x80x2) conforms, for example, to formula 
wherein for R1, R2, R3, R4, R5, R6, R8, R9, R10, R11, T, Z, Z1, Z2, b1, b2 and b3 each the above given meanings and preferences apply, and R29 is a radical of formula 
wherein R30 is hydrogen or methyl, R31 is C1-C12-alkylene, C1-C6-alkylenephenylene or phenylene-C1-C6-alkylene, or if w is 0 may also be a direct bond, w is 0 or 1, and X2 and X3 are each independently of the other xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94. R31 is preferably linear or branched C2-C6-alkylene, more preferably linear C2-C4-alkylene, and in particular 1,2-ethylene. w is preferably an integer of 1.
The compounds of formulae (1b*) and (1c*) are known, for example, from PCT application WO96/20919 or from U.S. Pat. No. 5,527,925.
The ethylenically unsaturated polymerization initiator may be applied to the initiator-modified material surface and polymerized there, for example, in analogy to the graft polymerization of the vinyl monomer having a reactive group as described above.
By means of the above described reaction step (a) of the process of the invention, the material surface is provided with a plurality of polymer brushes comprising polymerization initiator radicals. Each polymer chain of said brush-type structure contains polymerization initiator radicals at regular intervals (if the vinyl monomer comprising the reactive group is used without a vinyl comonomer, or if an ethylenically unsaturated polymerization initiator is used) or statistically distributed (if the vinyl monomer comprising the reactive group is used in combination with a vinyl comonomer).
A hydrophilic monomer in step (b) of the invention is understood to mean a monomer that typically produces as homopolymer a polymer that is water-soluble or capable of absorbing at least 10% by weight water.
Suitable hydrophilic vinyl comonomers include, without the following being an exhaustive list, hydroxy-substituted C1-C4-alkyl acrylates and methacrylates, acrylamide, methacryl-amide, mono- or di-C1-C4 alkylacrylamides and -methacrylamides, ethoxylated acrylates and methacrylates, hydroxy-substituted C1-C4-alkylacrylamides and methacrylamides, hydroxy-substituted C1-C4-alkyl vinyl ethers, sodium ethylenesulfonate, sodium styrenesulfonate, 2-acrylamido-2-methylpropanesulfonic acid, N-vinylpyrrole, N-vinylsuccinimide, N-vinylpyrrolidone, 2- or 4-vinylpyridine, vinylically unsaturated carboxylic acids having a total of from 3 to 5 carbon atoms, amino- (the term xe2x80x9caminoxe2x80x9d also including quaternary ammonium), mono-C1-C4-alkylamino- or di-C1-C4-alkylamino-C1-C4-alkyl acrylates and methacrylates, vinylacetate, allyl alcohol and the like. Preferred are, for example, hydroxy-substituted C2-C4alkyl (meth)acrylates, five- to seven-membered N-vinyl lactams, N,N-di-C1-C4-alkyl(meth)acrylamides, acrylic acid and methacrylic acid.
Examples of suitable hydrophilic vinyl comonomers include hydroxyethyl methacrylate, hydroxyethyl acrylate, acrylamide, methacrylamide, N,N-dimethylacrylamide, allyl alcohol, vinylpyridine, N-vinylpyrrolidine, glycerol methacrylate, N-(1,1-dimethyl-3-oxobutyl)-acrylamide and the like. Preferred hydrophilic vinyl comonomers are 2-hydroxyethyl methacylate, N-vinylpyrrolidone, N,N-dimethylacrylamide and acrylamide.
A suitable macromonomer according to step (b) of the process of the invention is, for example, of formula 
R32 is hydrogen, C1-C6-alkyl or a radical xe2x80x94COORxe2x80x2;
R, Rxe2x80x2 and R32xe2x80x2 are each independently of the other hydrogen or C1-C6-alkyl;
A is a direct bond or is a radical of formula
xe2x80x94C(O)xe2x80x94(A1)nxe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(5a) or
xe2x80x94(A2)mxe2x80x94NHxe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(5b); or
xe2x80x94(A2)mxe2x80x94Xxe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(5c); or
xe2x80x94C(O)xe2x80x94NHxe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(5d); or
xe2x80x94C(O)xe2x80x94X1-(alk*)-Xxe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(5e); or
A and R32, together with the adjacent double bond, are a radical of formula 
A1 is xe2x80x94Oxe2x80x94C2-C12-alkylene which is unsubstituted or substituted by hydroxy, or is xe2x80x94Oxe2x80x94C2-C12-alkylene-NHxe2x80x94C(O)xe2x80x94 or xe2x80x94Oxe2x80x942-C12-alkylene-Oxe2x80x94C(O)xe2x80x94NHxe2x80x94R33xe2x80x94NHxe2x80x94C(O)xe2x80x94 or xe2x80x94NH-(Alk*)-C(O)xe2x80x94, wherein (Alk*) is as defined above and R33 is linear or branched C1-C18-alkylene or unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted C6-C10-arylene, C7-C18-aralkylene, C6-C10-arylene-C1-C2-alkylene-C6-C10-arylene, C3-C8-cycloalkylene, C3-C8-cycloalkylene-C1-C6-alkylene, C3-C8-cycloalkylene-C1-C2-alkylene-C3-C8-cycloalkylene or C1-C6-alkylene-C3-C8-cycloalkylene-C1-C6-alkylene;
A2 is C1-C8-alkylene; phenylene or benzylene;
m and n are each independently of the other the number 0 or 1;
X, X1 and Xxe2x80x2 are each independently of the other a bivalent group xe2x80x94Oxe2x80x94 or xe2x80x94NRxe2x80x3, wherein Rxe2x80x3 is
hydrogen or C1-C6-alkyl;
(alk*) is C2-C12-alkylene;
and (oligomer) denotes
(i) the radical of a telomer of formula
-(alk)-S"Brketopenst"B"Brketclosest"p"Brketopenst"Bxe2x80x2"Brketclosest"qQxe2x80x83xe2x80x83(6a),
wherein (alk) is C2-C12-alkylene,
Q is a monovalent group that is suitable to act as a polymerization chain-reaction terminator,
p and q are each independently of another an integer from 0 to 350, wherein the total of (p+q) is an integer from 2 to 350, and B and Bxe2x80x2 are each independently of the other a 1,2-ethylene radical derivable from a copolymerizable vinyl monomer by replacing the vinylic double bond by a single bond, at least one of the radicals B and Bxe2x80x2 being substituted by a hydrophilic substituent; or
(ii) the radical of an oligomer of the formula 
wherein R19 is hydrogen or unsubstituted or hydroxy-substituted C1-C12-alkyl, u is an integer from 2 to 250 and Qxe2x80x2 is a radical of a polymerization initiator; or
(iii) the radical of formula 
wherein R19, X and u are as defined above, or
(iv) the radical of an oligomer of formula 
wherein R20 and R20xe2x80x2 are each independently C1-C4-alkyl, An is an anion, v is an integer from 2 to 250, and Qxe2x80x3 is a monovalent group that is suitable to act as a polymerization chain-reaction terminator; or
(v) the radical of an oligopeptide of formula
xe2x80x94CHR21xe2x80x94C(O)xe2x80x94NH)txe2x80x94CHR21xe2x80x94COOHxe2x80x83xe2x80x83(6d) or
xe2x80x94CHR21xe2x80x94NHxe2x80x94C(O)xe2x80x94CHR21)txe2x80x94NH2xe2x80x83xe2x80x83(6dxe2x80x2),
wherein R21 is hydrogen or C1-C4-alkyl which is unsubstituted or substituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o-, m- or p-hydroxyphenyl, imidazolyl, indolyl or a radical xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2 and t is an integer from 2 to 250, or the radical of an oligopeptide based on proline or hydroxyproline; or
(vi) the radical of a polyalkylene oxide of formula
(alkxe2x80x3xe2x80x94O)z-[CH2xe2x80x94CH2xe2x80x94O]r[CH2xe2x80x94CH(CH3)xe2x80x94O]sxe2x80x94R34xe2x80x83xe2x80x83(6e),
wherein R34 is hydrogen or C1-C24-alkyl, (alkxe2x80x3) is C2-C4-alkylene, z is 0 or 1, r and s are each independently an integer from 0 to 250 and the total of (r+s) is from 2 to 250; or
(vii) the radical of an oligosaccharide;
subject to the provisos that
A is not a direct bond if (oligomer) is a radical of formula (6a);
A is a radical of formula (5a), (5b) or (5d) or A and R32, together with the adjacent double bond, are a radical of formula (5f) if (oligomer) is a radical of formula (6b), (6c), (6d) or (6e) or is the radical of an oligosaccharide;
A is a direct bond if (oligomer) is a radical of formula (6bxe2x80x2); and
A is a radical of formula (5c) or (5e) if (oligomer) is a radical of formula (6dxe2x80x2).
The following preferences apply to the variables contained in the definition of the macromonomer of formula (4):
Rxe2x80x2 is preferably hydrogen or C1-C4-alkyl, more preferably hydrogen or C1-C2-alkyl and particularly preferably hydrogen.
R32 is preferably hydrogen, methyl or carboxyl, and particularly preferably hydrogen.
R is preferably hydrogen or methyl.
X is preferably a bivalent group xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94. X is particularly preferably the group xe2x80x94NHxe2x80x94 if (oligomer) is a radical of formula (6a); (6c) or (6d), and is particularly preferably the group xe2x80x94Oxe2x80x94 if (oligomer) is a radical of formula (6b) or (6e) or is the radical of an oligosaccharide. Xxe2x80x2 is preferably xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and more preferably xe2x80x94NHxe2x80x94. X1 is preferably xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94.
R33 as alkylene is preferably a linear or branched C3-C14alkylene radical, more preferably a linear or branched C4-C12alkylene radical and most preferably a linear or branched C6-C10-alkylene radical. Some preferred alkylene radicals are 1,4-butylene, 2,2-dimethyl-1,4-butylene, 1,5-pentylene, 2,2-dimethyl-1,5-pentylene, 1,6-hexylene, 2,2,3- or 2,2,4-trimethyl-1,5-pentylene, 2,2-dimethyl-1,6-hexylene, 2,2,3- or 2,2,4- or 2,2,5-trimethyl-1,6-hexylene, 2,2-dimethyl-1,7-heptylene, 2,2,3- or 2,2,4- or 2,2,5- or 2,2,6-trimethyl-1,7-heptylene, 1,8-octylene, 2,2-dimethyl-1,8-octylene and 2,2,3- or 2,2,4- or 2,2,5- or 2,2,6- or 2,2,7-trimethyl-1,8-octylene.
When R33 is arylene, it is, for example, naphthylene or especially phenylene, each of which may be substituted, for example, by C1-C4-alkyl or by C1-C4-alkoxy. Preferably, R33 as arylene is 1,3- or 1,4-phenylene that is unsubstituted or substituted by C1-C4-alkyl or by C1-C4-alkoxy in the ortho-position to at least one linkage site.
R33 as aralkylene is preferably naphthylalkylene and most preferably phenylalkylene. The alkylene group in aralkylene contains preferably from 1 to 12, more preferably from 1 to 6 and most preferably from 1 to 4 carbon atoms. Most preferably, the alkylene group in aralkylene is methylene or ethylene.
When R33 is cycloalkylene, it is preferably C5-C6-cycloalkylene and most preferably cyclohexylene that is unsubstituted or substituted by methyl.
When R33 is cycloalkylene-alkylene, it is preferably cyclopentylene-C1-C4-alkylene and especially cyclohexylene-C1-C4-alkylene, each unsubstituted or mono- or poly-substituted by C1-C4-alkyl, especially methyl. More preferably, the group cycloalkylene-alkylene is cyclohexylene-ethylene and, most preferably, cyclohexylene-methylene, each unsubstituted or substituted in the cyclohexylene radical by from 1 to 3 methyl groups.
When R33 is alkylene-cycloalkylene-alkylene, it is preferably C1-C4-alkylene-cyclopentylene-C1-C4-alkylene and especially C1-C4-alkylene-cyclohexylene-C1-C4-alkylene, each unsubstituted or mono- or poly-substituted by C1-C4-alkyl, especially methyl. More preferably, the group alkylene-cycloalkylene-alkylene is ethylene-cyclohexylene-ethylene and, most preferably, is methylene-cyclohexylene-methylene, each unsubstituted or substituted in the cyclohexylene radical by from 1 to 3 methyl groups.
R33 as C3-C8-cycloalkylene-C1-C2-alkylene-C3-C8-cycloalkylene or C6-C10-arylene-C1-C2-alkylene-C6-C10-arylene is preferably C5-C6-cycloalkylene-methylene-C5-C6-cycloalkylene or phenylene-methylene-phenylene, each of which may be unsubstituted or substituted in the cycloalkyl or phenyl ring by one or more methyl groups.
The radical R33 has a symmetrical or, preferably, an asymmetrical structure. A preferred group of radicals R11 comprises those, wherein R33 is linear or branched C6-C10alkylene; cyclohexylene-methylene or cyclohexylene-methylene-cyclohexylene each unsubstituted or substituted in the cyclohexyl moiety by from 1 to 3 methyl groups; or phenylene or phenylene-methylene-phenylene each unsubstituted or substituted in the phenyl moiety by methyl. The bivalent radical R33 is derived preferably from a diisocyanate and most preferably from a diisocyanate selected from the group isophorone diisocyanate (IPDI), toluylene-2,4-diisocyanate (TDI), 4,4xe2x80x2-methylenebis(cyclohexyl isocyanate), 1,6-diisocyanato-2,2,4-trimethyl-n-hexane (TMDI), methylenebis(phenyl isocyanate), methylenebis(cyclohexyl-4-isocyanate) and hexamethylene diisocyanate (HMDI).
Preferred meanings of A1 are unsubstituted or hydroxy-substituted xe2x80x94Oxe2x80x94C2-C8-alkylene or a radical xe2x80x94Oxe2x80x94C2-C6-alkylenexe2x80x94NHxe2x80x94C(O)xe2x80x94 and particularly xe2x80x94Oxe2x80x94(CH2)2-4xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94 or a radical xe2x80x94Oxe2x80x94(CH2)2-4xe2x80x94NHxe2x80x94C(O)xe2x80x94. A particularly preferred meaning of A1 is the radical xe2x80x94Oxe2x80x94(CH2)2xe2x80x94NHxe2x80x94C(O)xe2x80x94.
A2 is preferably C1-C6-alkylene, phenylene or benzylene, more preferably C1-C4-alkylene and even more preferably C1-C2-alkylene.
n is an integer of 0 or preferably 1. m is preferably an integer of 1.
R32xe2x80x2 is preferably hydrogen or methyl and particularly preferably hydrogen.
In case that (oligomer) is a radical of formula (6a), (6b), (6c), (6d) or (6e) or is the radical of an oligosaccharide, is A preferably a radical of formula (5a) or (5b) and particularly preferably a radical of formula (5a), wherein the above given meanings and preferences apply for the variables contained therein.
A preferred group of hydrophilic macromonomers according to the invention comprises compounds of the above formula (4), wherein R is hydrogen or methyl, R32 is hydrogen, methyl or carboxyl, R32xe2x80x2 is hydrogen, A is a radical of the formula (5a) or (5b) and (oligomer) is a radical of formula (6a), (6b), (6c), (6d) or (6e) or is the radical of an oligosaccharide. An even more preferred group of hydrophilic macromonomers comprises compounds of the above formula (4), wherein R is hydrogen or methyl, R32 and R32xe2x80x2 are each hydrogen, A is a radical of the formula (5a) and (oligomer) is a radical of formula (6a). A further group of preferred macromonomers comprises compounds of formula (4), wherein A is a radical of formula (5e) above and (oligomer) is a radical of formula (6a).
(alk) and (alk*) are each independently preferably C2-C8-alkylene, more preferably C2-C6-alkylene, even more preferably C2-C4-alkylene and particularly preferably 1,2-ethylene. The alkylene radicals (alk) and (alk*) may be branched or preferably linear alkylene radicals.
Q is for example hydrogen.
The total of (p+q) is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50. In a preferred embodiment of the invention q is 0 and p is an integer from 2 to 250, preferably from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50.
Suitable hydrophilic substituents of the radicals B or Bxe2x80x2 may be non-ionic, anionic, cationic or zwitterionic substituents. Accordingly, the telomer chain of formula (5a) that contains monomer units B and/or Bxe2x80x2 may be a charged chain containing anionic, cationic and/or zwitterionic groups or may be an uncharged chain. In addition, the telomer chain may comprise a copolymeric mixture of uncharged and charged units. The distribution of the charges within the telomer, if present, may be random or blockwise.
In one preferred embodiment of the invention, the telomer radical of formula (6a) is composed solely of non-ionic monomer units B and/or Bxe2x80x2. In another preferred embodiment of the invention, the telomer radical of formula (6a) is composed solely of ionic monomer units B and/or Bxe2x80x2, for example solely of cationic monomer units or solely of anionic monomer units. Still another preferred embodiment of the invention is directed to telomer radicals of formula (6a) comprising nonionic units B and ionic units Bxe2x80x2.
Suitable non-ionic substituents of B or Bxe2x80x2 include for example a radical C1-C6-alkyl which is substituted by one or more same or different substituents selected from the group consisting of xe2x80x94OH, C1-C4-alkoxy and xe2x80x94NR23R23xe2x80x2, wherein R23 and R23xe2x80x2 are each independently of another hydrogen or unsubstituted or hydroxy-substituted C1-C6-alkyl or phenyl; phenyl which is substituted by hydroxy, C1-C4-alkoxy or xe2x80x94NR23R23xe2x80x2, wherein R23 and R23xe2x80x2 are as defined above; a radical xe2x80x94COOY, wherein Y is C1-C24-alkyl which is unsubstituted or substituted, for example, by hydroxy, C1-C4-alkoxy, xe2x80x94Oxe2x80x94Si(CH3)3, xe2x80x94NR23R23xe2x80x2 wherein R23 and R23xe2x80x2 are as defined above, a radical xe2x80x94Oxe2x80x94(CH2CH2O)1-24-E wherein E is hydrogen or C1-C6-alkyl, or a radical xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G, wherein xe2x80x94Oxe2x80x94G is the radical of a saccharide with 1 to 8 sugar units or is a radical xe2x80x94Oxe2x80x94(CH2CH2O)1-24-E, wherein E is as defined above, or Y is C5-C8-cycloalkyl which is unsubstituted or substituted by C1-C4-alkyl or C1-C4-alkoxy, or is unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted phenyl or C7-C12-aralkyl; xe2x80x94CONY1Y2 wherein Y1 and Y2 are each independently hydrogen, C1-C12-alkyl, which is unsubstituted or substituted for example by hydroxy, C1-C4-alkoxy or a radical xe2x80x94Oxe2x80x94(CH2CH2O)1-24-E wherein E is as defined above, or Y1 and Y2 together with the adjacent N-atom form a five- or six-membered heterocyclic ring having no additional heteroatom or one additional oxygen or nitrogen atom; a radical xe2x80x94OY3, wherein Y3 is hydrogen; or C1-C12-alkyl which is unsubstituted or substituted by xe2x80x94NR23R23xe2x80x2; or is a radical xe2x80x94C(O)xe2x80x94C1-C4-alkyl; and wherein R23 and R23xe2x80x2 are as defined above; or a five- to seven-membered heterocyclic radical having at least one N-atom and being bound in each case via said nitrogen atom.
Suitable anionic substituents of B or Bxe2x80x2 include for example C1-C6-alkyl which is substituted by xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94OPO3H2 and xe2x80x94COOH; phenyl which is substituted by one or more same or different substituents selected from the group consisting of xe2x80x94SO3H, xe2x80x94COOH, xe2x80x94OH and xe2x80x94CH2xe2x80x94SO3H; xe2x80x94COOH; a radical xe2x80x94COOY4, wherein Y4 is C1-C24-alkyl which is substituted for example by xe2x80x94COOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94OPO3H2 or by a radical xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94Gxe2x80x2 wherein Gxe2x80x2 is the radical of an anionic carbohydrate; a radical xe2x80x94CONY5Y6 wherein Y5 is C1-C24-alkyl which is substituted by xe2x80x94COOH, xe2x80x94SO3H, xe2x80x94OSO3H, or xe2x80x94OPO3H2 and Y6 independently has the meaning of Y5 or is hydrogen or C1-C12-alkyl; or xe2x80x94SO3H; or a salt thereof, for example a sodium, potassium, ammonium or the like salt thereof.
Suitable cationic substituents of B or Bxe2x80x2 include C1-C12-alkyl which is substituted by a radical xe2x80x94NR23R23xe2x80x2R23xe2x80x3+Anxe2x88x92, wherein R23, R23xe2x80x2 and R23xe2x80x3 are each independently of another hydrogen or unsubstituted or hydroxy-substituted C1-C6-alkyl or phenyl, and Anxe2x88x92 is an anion; or a radical xe2x80x94C(O)OY7, wherein Y7 is C1-C24-alkyl which is substituted by xe2x80x94NR23R23xe2x80x2R23xe2x80x3+Anxe2x88x92 and is further unsubstituted or substituted for example by hydroxy, wherein R23 R23xe2x80x2, R23xe2x80x3 and Anxe2x88x92 are as defined above.
Suitable zwitterionic substituents of B or Bxe2x80x2 include a radical xe2x80x94R24xe2x80x94Zw, wherein R24 is a direct bond or a functional group, for example a carbonyl, carbonate, amide, ester, dicarboanhydride, dicarboimide, urea or urethane group; and Zw is an aliphatic moiety comprising one anionic and one cationic group each.
The following preferences apply to the hydrophilic substituents of B and Bxe2x80x2:
(i) Non-ionic Substituents:
Preferred alkyl substituents of B or Bxe2x80x2 are C1-C4-alkyl, in particular C1-C2-alkyl, which is substituted by one or more substituents selected from the group consisting of xe2x80x94OH and xe2x80x94NR23R23xe2x80x2, wherein R23 and R23xe2x80x2 are each independently of another hydrogen or C1-C4-alkyl, preferably hydrogen, methyl or ethyl and particularly preferably hydrogen or methyl, for example xe2x80x94CH2xe2x80x94NH2, xe2x80x94CH2xe2x80x94N(CH3)2.
Preferred phenyl substituents of B or Bxe2x80x2 are phenyl which is substituted by xe2x80x94NH2 or N(C1-C2-alkyl)2, for example o-, m- or p-aminophenyl.
In case that the hydrophilic substituent of B or Bxe2x80x2 is a radical xe2x80x94COOY, Y as optionally substituted alkyl is preferably C1-C12-alkyl, more preferably C1-C6-alkyl, even more preferably C1-C4-alkyl and particularly preferably C1-C2-alkyl, each of which being unsubstituted or substituted as mentioned above. In case that the alkyl radical Y is substituted by xe2x80x94NR23R23xe2x80x2, the above-given meanings and preferences apply for R23 and R23xe2x80x2. Examples of suitable saccharide substituents xe2x80x94Oxe2x80x94G of the alkyl radical Y that is substituted by xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G are the radical of a mono- or disaccharide, for example glucose, acetyl glucose, methyl glucose, glucosamine, N-acetyl glucosamine, glucono lactone, mannose, galactose, galactosamine, N-acetyl galactosamine, fructose, maltose, lactose, fucose, saccharose or trehalose, the radical of an anhydrosaccharide such as levoglucosan, the radical of a glucosid such as octylglucosid, the radical of a sugar alcohol such as sorbitol, the radical of a sugar acid derivative such as lactobionic acid amide, or the radical of an oligosaccharide with a maximum of 8 sugar units, for example fragments of a cyclodextrin, starch, chitosan, maltotriose or maltohexaose. The radical xe2x80x94Oxe2x80x94G preferably denotes the radical of a mono- or disaccharide or the radical of a cyclodextrin fragment with a maximum of 8 sugar units. Particular preferred saccharide radicals xe2x80x94Oxe2x80x94G are the radical of trehalose or the radical of a cyclodextrin fragment. In case that the alkyl radical Y is substituted by a radical xe2x80x94Oxe2x80x94(CH2CH2O)1-24-E or xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is xe2x80x94Oxe2x80x94(CH2CH2O)1-24-E, the number of (CH2CH2O) units is preferably from 1 to 12 in each case and more preferably from 2 to 8. E is preferably hydrogen or C1-C2-alkyl.
Y as C5-C8-cycloalkyl is for example cyclopentyl or preferably cyclohexyl, each of which being unsubstituted or substituted for example by 1 to 3 C1-C2-alkyl groups. Y as C7-C12-aralkyl is for example benzyl.
Preferred nonionic radicals xe2x80x94COOY are those wherein Y is C1-C6-alkyl; or C2-C6-alkyl which is substituted by one or two substituents selected from the group consisting of hydroxy; C1-C2-alkoxy; xe2x80x94Oxe2x80x94Si(CH3)3; and xe2x80x94NR23R23xe2x80x2 wherein R23 and R23xe2x80x2 are each independently of another hydrogen or C1-C4-alkyl; or Y is a radical xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(CH2CH2O)1-12-E wherein E is hydrogen or C1-C2-alkyl; or is a radical xe2x80x94C2-C4-alkylenexe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G, wherein xe2x80x94Oxe2x80x94G is the radical of a saccharide.
More preferred non-ionic radicals xe2x80x94COOY are those wherein Y is C1-C4-alkyl; or C2-C4-alkyl which is substituted by one or two substituents selected from the group consisting of xe2x80x94OH and xe2x80x94NR23R23xe2x80x2 wherein R23 and R23xe2x80x2 are each independently of another hydrogen or C1-C2-alkyl; or a radical xe2x80x94CH2CH2xe2x80x94Oxe2x80x94(CH2CH2O)1-12-E wherein E is hydrogen or C1-C2-alkyl; or is a radical xe2x80x94C2-C4-alkylenexe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of a saccharide.
Particularly preferred radicals xe2x80x94COOY comprise those wherein Y is C1-C2-alkyl, particularly methyl; or C2-C3-alkyl, which is unsubstituted or substituted by hydroxy or N,N-di-C1-C2-alkylamino, or is a radical -C2-C3-alkylenexe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of trehalose or the radical of a cyclodextrin fragment with a maximum of 8 sugar units.
Preferred non-ionic substituents xe2x80x94C(O)xe2x80x94NY1Y2 of B or Bxe2x80x2 are those wherein Y1 and Y2 are each independently of the other hydrogen or C1-C6-alkyl which is unsubstituted or substituted by hydroxy; or Y1 and Y2 together with the adjacent N-atom form a heterocyclic 6-membered ring having no further heteroatom or having one further N- or O-atom. Even more preferred meanings of Y1 and Y2, independently of each other, are hydrogen or C1-C4-alkyl which is unsubstituted or substituted by hydroxy; or Y1 and Y2 together with the adjacent N-atom form a Nxe2x80x94C1-C2-alkylpiperazino or morpholino ring. Particularly preferred non-ionic radicals xe2x80x94C(O)xe2x80x94NY1Y2 are those wherein Y1 and Y2 are each independently of the other hydrogen or C1-C2-alkyl; or Y1 and Y2 together with the adjacent N-atom form a morpholino ring.
Preferred non-ionic substituents xe2x80x94OY3 of B or Bxe2x80x2 are those wherein Y3 is hydrogen, C1-C4-alkyl which is unsubstituted or substituted by xe2x80x94NH2 or xe2x80x94N(C1-C2-alkyl)2, or is a group xe2x80x94C(O)C1-C2-alkyl. Y3 is particularly preferred hydrogen or acetyl.
Preferred non-ionic heterocyclic substituents of B or Bxe2x80x2 are a 5- or 6-membered heteroaromatic or heteroaliphatic radical having one N-atom and in addition no further heteroatom or an additional N- or O-heteroatom, or is a 5 to 7-membered lactame. Examples of such heterocyclic radicals are N-pyrrolidonyl, 2- or 4-pyridinyl, 2-methyl pyridin-5-yl, 2-, 3- oder 4-hydroxypyridinyl, N-xcex5-caprolactamyl, N-imidazolyl, 2-methylimidazol-1-yl, N-morpholinyl or 4-N-methylpiperazin-1-yl, particularly N-morpholinyl or N-pyrrolidonyl.
A group of preferred non-ionic substituents of B or Bxe2x80x2 comprises C1-C2-alkyl, which is unsubstituted or substituted by xe2x80x94OH or xe2x80x94NR23R23xe2x80x2, wherein R23 and R23xe2x80x2 are each independently of the other hydrogen or C1-C2-alkyl; a radical xe2x80x94COOY wherein Y is C1-C4-alkyl; C2-C4-alkyl which is substituted by xe2x80x94OH, xe2x80x94NR23R23xe2x80x2 wherein R23 and R23xe2x80x2 are each independently of another hydrogen or C1-C2-alkyl, or Y is a radical xe2x80x94C2-C4-alkylenexe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of a saccharide; a radical xe2x80x94C(O)xe2x80x94NY1Y2, wherein Y1 and Y2 are each independently of the other hydrogen or C1-C6-alkyl which is unsubstituted or substituted by hydroxy, or Y1 and Y2 together with the adjacent N-atom form a heterocyclic 6-membered ring having no further heteroatom or having one further N- or O-atom; a radical xe2x80x94OY3, wherein Y3 is hydrogen, C1-C4-alkyl which is unsubstituted or substituted by xe2x80x94NH2 or xe2x80x94N(C1-C2-alkyl)2, or is a group xe2x80x94C(O)C1-C2-alkyl; or a 5- or 6-membered heteroaromatic or heteroaliphatic radical having one N-atom and in addition no further heteroatom or an additional N-, O- or S-heteroatom, or a 5 to 7-membered lactame.
A group of more preferred non-ionic substituents of B or Bxe2x80x2 comprises a radical xe2x80x94COOY, wherein Y is C1-C2-alkyl, C2-C3-alkyl, which is substituted by hydroxy, amino or N,N-di-C1-C2-alkylamino, or is a radical xe2x80x94C2-C4-alkylenexe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of trehalose or a cyclodextrin fragment with a maximum of 8 sugar units; a radical xe2x80x94COxe2x80x94NY1Y2, wherein Y1 and Y2 are each independently of the other hydrogen or C1-C4-alkyl which is unsubstituted or substituted by hydroxy, or Y1 and Y2 together with the adjacent N-atom form a N-C1-C2-alkylpiperazino or morpholino ring; or a heterocyclic radical selected from the group consisting of N-pyrrolidonyl, 2- or 4-pyridinyl, 2-methylpyridin-5-yl, 2-, 3- oder 4-hydroxypyridinyl, N-xcex5-caprolactamyl, N-imidazolyl, 2-methylimidazol-1-yl, N-morpholinyl and 4-N-methylpiperazin-1-yl.
A particularly preferred group of non-ionic substituents of B or Bxe2x80x2 comprises the radicals xe2x80x94CONH2, xe2x80x94CON(CH3)2, 
xe2x80x94CONHxe2x80x94(CH2)2xe2x80x94OH, xe2x80x94COOxe2x80x94(CH2)2xe2x80x94N(CH3)2, and xe2x80x94COO(CH2)2-4xe2x80x94NHC(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of trehalose.
(ii) Anionic Substituents:
Preferred anionic substituents of B or Bxe2x80x2 are C1-C4-alkyl, in particular C1-C2-alkyl, which is substituted by one or more substituents selected from the group consisting of xe2x80x94SO3H and xe2x80x94OPO3H2, for example xe2x80x94CH2xe2x80x94SO3H; phenyl which is substituted by xe2x80x94SO3H or sulfomethyl, for example o-, m- or p-sulfophenyl or o-, m- or p-sulfomethylphenyl; xe2x80x94COOH; a radical xe2x80x94COOY4, wherein Y4 is C2-C6-alkyl which is substituted by xe2x80x94COOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94OPO3H2, or by a radical xe2x80x94NHxe2x80x94C(O)xe2x80x94Oxe2x80x94Gxe2x80x2 wherein Gxe2x80x2 is the radical of lactobionic acid, hyaluronic acid or sialic acid, in particular C2-C4-alkyl which is substituted by xe2x80x94SO3H or xe2x80x94OSO3H; a radical xe2x80x94CONY5Y6 wherein Y5 is C1-C6-alkyl substituted by sulfo, in particular C2-C4-alkyl substituted by sulfo, and Y6 is hydrogen, for example the radical xe2x80x94C(O)xe2x80x94NHxe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94SO3H; or xe2x80x94SO3H; or a suitable salt thereof. Particular preferred anionic substituents of B or Bxe2x80x2 are xe2x80x94COOH, xe2x80x94SO3H, o-, m- or p-sulfophenyl, o-, m- or p-sulfomethylphenyl or a radical xe2x80x94CONY5Y6 wherein Y5 is C2-C4-alkyl substituted by sulfo, and Y6 is hydrogen.
(iii) Cationic Substituents:
Preferred cationic substituents of B or Bxe2x80x2 are C1-C4-alkyl, in particular C1-C2-alkyl, which is in each case substituted by xe2x80x94NR23R23xe2x80x2R23xe2x80x3+Anxe2x88x92; or a radical xe2x80x94C(O)OY7 wherein Y7 is C2-C6-alkyl, in particular C2-C4-alkyl, which is in each case substituted by xe2x80x94NR23R23xe2x80x2R23xe2x80x3+Anxe2x88x92 and is further unsubstituted or substituted by hydroxy. R23, R23xe2x80x2 and R23xe2x80x3 are each independently of another preferably hydrogen or C1-C4-alkyl, more preferably methyl or ethyl and particularly preferably methyl. Examples of suitable anions Anxe2x88x92 are Halxe2x88x92, wherein Hal is halogen, for example Brxe2x88x92, Fxe2x88x92, Jxe2x88x92 or particularly Clxe2x88x92, furthermore HCO3xe2x88x92, CO32xe2x88x92, H2PO3xe2x88x92, HPO32xe2x88x92, PO33xe2x88x92, HSO4xe2x88x92, SO42xe2x88x92 or the radical of an organic acid such as OCOCH3xe2x88x92 and the like. A particularly preferred cationic substituent of B or Bxe2x80x2 is a radical xe2x80x94C(O)OY7 wherein Y7 is C2-C4-alkyl, which is substituted by xe2x80x94N(C1-C2-alkyl)3+Anxe2x88x92and is further substituted by hydroxy, and An is an anion, for example the radical xe2x80x94C(O)Oxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(CH3)3+Anxe2x88x92.
(iv) zwitterionic substituents xe2x80x94R24xe2x80x94Zw:
R24 is a preferably a carbonyl, ester or amide functional group and more preferably an ester group xe2x80x94C(O)xe2x80x94Oxe2x80x94.
Suitable anionic groups of the moiety Zw are for example xe2x80x94COOxe2x88x92, xe2x80x94SO3xe2x88x92, xe2x80x94OSO3xe2x88x92, xe2x80x94OPO3Hxe2x88x92 or bivalent xe2x80x94Oxe2x80x94PO2xe2x88x92 or xe2x80x94Oxe2x80x94PO2xe2x88x92xe2x80x94Oxe2x80x94, preferably a group xe2x80x94COOxe2x88x92 or xe2x80x94SO3xe2x88x92 or a bivalent group xe2x80x94Oxe2x80x94PO2xe2x88x92, and in particular a group xe2x80x94SO3xe2x88x92. Suitable cationic groups of the moiety Zw are for example a group xe2x80x94NR23R23xe2x80x2R23xe2x80x3+ or a bivalent group xe2x80x94NR23R23xe2x80x2+xe2x80x94, wherein R23, R23xe2x80x2 and R23xe2x80x3 are as defined above, and are each independently of the other, preferably hydrogen or C1-C6-alkyl, preferably hydrogen or C1-C4-alkyl and most preferably each methyl or ethyl.
The moiety Zw is for example C2-C30-alkyl, preferably C2-C12-alkyl, and more preferably C3-C8-alkyl, which is in each case uninterrupted or interrupted by xe2x80x94Oxe2x80x94 and substituted or interrupted by one of the above-mentioned anionic and cationic groups each, and, in addition, is further unsubstituted or substituted by a radical xe2x80x94OY8, wherein Y8 is hydrogen or the acyl radical of a carboxylic acid.
Y8 is preferably hydrogen or the acyl radical of a higher fatty acid.
Zw is preferably C2-C12-alkyl and even more preferably C3-C8-alkyl which is substituted or interrupted by one of the above-mentioned anionic and cationic groups each, and in addition may be further substituted by a radical xe2x80x94OY8.
A preferred group of zwitter-ionic substituents xe2x80x94R24xe2x80x94Zw corresponds to the formula
xe2x80x94C(O)Oxe2x80x94(alkxe2x80x2xe2x80x3)xe2x80x94N(R23)2+xe2x80x94(alkxe2x80x2)xe2x80x94Anxe2x88x92 or
xe2x80x94C(O)Oxe2x80x94(alkxe2x80x3)xe2x80x94Oxe2x80x94PO2xe2x88x92xe2x80x94(O)0-1xe2x80x94(alkxe2x80x2xe2x80x3)xe2x80x94N(R23)3+
wherein R23 is hydrogen or C1-C6-alkyl; Anxe2x88x92 is an anionic group xe2x80x94COOxe2x88x92, xe2x80x94SO3xe2x88x92, xe2x80x94OSO3xe2x88x92 or xe2x80x94OPO3Hxe2x88x92, preferably xe2x80x94COOxe2x88x92 or xe2x80x94SO3xe2x88x92 and most preferably xe2x80x94SO3xe2x88x92, alkxe2x80x2 is C1-C12-alkylene, (alkxe2x80x3) is C2-C24-alkylene which is unsubstituted or substituted by a radical xe2x80x94OY8, Y8 is hydrogen or the acyl radical of a carboxylic acid, and (alkxe2x80x2xe2x80x3) is C2-C8-alkylene.
(alkxe2x80x2) is preferably C2-C8-alkylene, more preferably C2-C6-alkylene and most preferably C2-C4-alkylene. (alkxe2x80x3) is preferably C2-C12-alkylene, more preferably C2-C6-alkylene and particularly preferably C2-C3-alkylene which is in each case unsubstituted or substituted by hydroxy or by a radical xe2x80x94OY8. (alkxe2x80x2xe2x80x3) is preferably C2-C4-alkylene and more preferably C2-C3-alkylene. R9 is hydrogen or C1-C4-alkyl, more preferably methyl or ethyl and particularly preferably methyl. A preferred zwitterionic substituent of B or Bxe2x80x2 is of formula
xe2x80x94C(O)Oxe2x80x94CH2xe2x80x94CH(OY8)xe2x80x94CH2xe2x80x94Oxe2x80x94PO2xe2x88x92xe2x80x94(CH2)2xe2x80x94N(CH3)3+,
wherein Y8 is hydrogen or the acyl radical of a higher fatty acid.
B denotes for example a radical of formula 
wherein R25 is hydrogen or C1-C4-alkyl, preferably hydrogen or methyl; R26 is a hydrophilic substituent, wherein the above given meanings and preferences apply; R27 is C1-C4-alkyl, phenyl or a radical xe2x80x94C(O)OY9, wherein Y9 is hydrogen or unsubstituted or hydroxy-substituted C1-C4-alkyl; and R28 is a radical xe2x80x94C(O)Y9xe2x80x2 or xe2x80x94CH2xe2x80x94C(O)OY9xe2x80x2 wherein Y9xe2x80x2 independently has the meaning of Y9.
R27 is preferably C1-C2-alkyl, phenyl or a group xe2x80x94C(O)OY9. R28 is preferably a group xe2x80x94C(O)OY9xe2x80x2 or xe2x80x94CH2xe2x80x94C(O)OY9xe2x80x2 wherein Y9 and Y9xe2x80x2 are each independently of the other hydrogen, C1-C2-alkyl or hydroxy-C1-C2-alkyl. Particularly preferred xe2x80x94CHR27xe2x80x94CHR28xe2x80x94 units according to the invention are those wherein R27 is methyl or a group xe2x80x94C(O)OY9 and R28 is a group xe2x80x94C(O)OY9xe2x80x2 or xe2x80x94CH2xe2x80x94C(O)OY9xe2x80x2 wherein Y9 and Y9xe2x80x2 are each hydrogen, C1-C2-alkyl or hydroxy-C1-C2-alkyl.
Bxe2x80x2 independently may have one of the meanings given above for B.
If (oligomer) is a radical of formula (6a), the radical -(alk)-Sxe2x80x94[B]pxe2x80x94[Bxe2x80x2]qxe2x80x94Q preferably denotes a radical of formula 
even more preferably of the formula 
wherein for R25, R26, Q, p and q the above-given meanings and preferences apply, for R25xe2x80x2 independently the meanings and preferences given before for R25 apply, and for R26xe2x80x2 independently the meanings and preferences given before for R26 apply.
A preferred group of suitable hydrophilic macromonomers according to step (b) of the invention comprises compounds of formula 
wherein R is hydrogen or methyl, A1 is xe2x80x94Oxe2x80x94(CH2)2-4xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94 or a radical xe2x80x94Oxe2x80x94(CH2)2-4xe2x80x94NHxe2x80x94C(O)xe2x80x94, X is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, (alk) is C2-C4-alkylene, Q is a monovalent group that is suitable to act as a polymerization chain-reaction terminator, p is an integer from 5 to 50, R25 and R25xe2x80x2 are each independently of the other hydrogen or methyl, and for R26 and R26xe2x80x2 each independently the above given meanings and preferences apply.
A particularly preferred embodiment of the invention relates to hydrophilic macromonomers of the formula 
wherein for R, R25, R26, Q, (alk) and p the above-given meanings and preferences apply. A particularly preferred group of hydrophilic macromonomers are compounds of the above formula (4b) wherein R is hydrogen or methyl, (alk) is C2-C4-alkylene, R25 is hydrogen or methyl, p is an integer of 5 to 50, Q is as defined before, and for R26 the above given meanings and preferences apply; in particular R26 of this embodiment is a radical xe2x80x94CONH2, xe2x80x94CON(CH3)2 or 
If (oligomer) is a radical (ii) of formula (6b), Qxe2x80x2 in formula (6b) is for example C1-C12-alkyl, phenyl or benzyl, preferably C1-C2-alkyl or benzyl and in particular methyl. R19 is preferably unsubstituted or hydroxy-substituted C1-C4-alkyl and in particular methyl. u is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50.
If (oligomer) is a radical of formula (6bxe2x80x2), the above given meanings and preferences apply for the variables R19 and u contained therein. X in formula (6bxe2x80x2) is preferably hydroxy or amino.
If (oligomer) denotes a radical (iv) of formula (6c), R20 and R20xe2x80x2 are each preferably ethyl or in particular methyl; v is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50; Qxe2x80x3 is for example hydrogen; and Anxe2x88x92 is as defined before.
If (oligomer) denotes an oligopeptide radical (v) of formula (6d) or 6dxe2x80x2), R21 is for example hydrogen, methyl, hydroxymethyl, carboxymethyl, 1-hydroxyethyl, 2-carboxyethyl, isopropyl, n-, sec. or iso-butyl, 4-amino-n-butyl, benzyl, p-hydroxybenzyl, imidazolylmethyl, indolylmethyl or a radical xe2x80x94(CH2)3xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2. t is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50.
If (oligomer) denotes a polyoxyalkylene radical (vi) of formula (6e), R34 is preferably hydrogen or C1-C18-alkyl, more preferably hydrogen or C1-C12-alkyl, even more preferably hydrogen, methyl or ethyl, and particularly preferably hydrogen or methyl. (alkxe2x80x3) is preferably a C2-C3-alkylene radical. z is preferably 0. r and s are each independently preferably an integer from 0 to 100 wherein the total of (r+s) is 5 to 100. r and s are each independently more preferably an integer from 0 to 50 wherein the total of (r+s) is 8 to 50. In a particularly preferred embodiment of the polyoxyalkylene radicals (oligomer), r is an integer from 8 to 50 and particularly 9 to 25, and s is 0.
(oligomer) as the radical of an oligosaccharide (vii) may be, for example, a di- or polysaccharide including carbohydrate containing fragments from a biopolymer. Examples are the radical of a cyclodextrin, trehalose, cellobiose, maltotriose, maltohexaose, chitohexaose or a starch, hyaluronic acid, deacetylated hyaluronic acid, chitosan, agarose, chitin 50, amylose, glucan, heparin, xylan, pectin, galactan, glycosaminoglycan, mucin, dextran, aminated dextran, cellulose, hydroxyalkylcellulose or carboxyalkylcellulose oligomer, each of which with a molecular weight average weight of, for example, up to 25000, preferably up to 10000. Preferably the oligosaccharide according to (vii) is the radical of a cyclodextrin with a maximum of 8 sugar units.
Formulae (6a), (6axe2x80x2) or (6e) are to be understood as a statistic description of the respective oligomeric radicals, that is to say, the orientation of the monomers and the sequence of the monomers (in case of copolymers) are not fixed in any way by said formulae. The arrangement of B and Bxe2x80x2 in formula (6a) or of the ethyleneoxide and propyleneoxide units in formula (6e) thus in each case may be random or blockwise.
The weight average molecular weight of the hydrophilic macromonomer according to step (b) depends principally on the desired properties and is for example from 300 to 25000, preferably from 300 to 12000, more preferably from 300 to 8000, even more preferably from 300 to 5000, and particularly preferably from 500 to 4000.
The macromonomers of formula (4) may be prepared by methods known per se. For example, the compounds of formula (4) wherein A is a radical of formula (5a), (5b) or (5d) are obtainable by reacting a compound of formula 
wherein R, R32 and R32xe2x80x2 each have the above-given meaning and A* is, for example, a group xe2x80x94C(O)xe2x80x94A**, wherein A** is halogen, particularly chlorine, an ester group an oxyalkylene radical comprising an epoxy group, for example the radical 
or is a radical xe2x80x94Oxe2x80x94C2-C12-alkylenexe2x80x94Nxe2x95x90Cxe2x95x90O; or A* is a radical xe2x80x94(A2)mxe2x80x94Nxe2x95x90Cxe2x95x90O, wherein A2 and m have the above-given meaning, with a compound of formula
HXxe2x80x94(oligomer)xe2x80x83xe2x80x83(9),
wherein X has the above-given meaning.
The reactions of a compound of formula (8) having a carboxylic acid halide group, an epoxy group or an isocyanato group with an amino or hydroxy compound of formula (9) are well-known in the art and may be carried out as desribed in textbooks of organic chemistry. For example, the reaction of an isocyanato derivative of formula (8) with a compound of formula (9) may be carried out in an inert organic solvent such as an optionally halogenated hydrocarbon, for example petroleum ether, methylcyclohexane, toluene, chloroform, methylene chloride and the like, or an ether, for example diethyl ether, tetrahydrofurane, dioxane, or a more polar solvent such as DMSO, DMA, N-methylpyrrolidone or even a lower alcohol, at a temperature of from 0 to 100xc2x0 C., preferably from 0 to 50xc2x0 C. and particularly preferably at room temperature, optionally in the presence of a catalyst, for example a tertiary amine such as triethylamine or tri-n-butylamine, 1,4-diazabicyclooctane, or a tin compound such as dibutyltin dilaurate or tin dioctanoate. In addition, the reaction of an isocyanato derivative of formula (8) with a compound of formula (9) wherein xe2x80x94XH is an amino group also may be carried out in an aqueous solution in the absence of a catalyst. It is advantageous to carry out the above reactions under an inert atmosphere, for example under an nitrogen or argon atmosphere.
Moreover, the macromonomers of formula (4) wherein A is a radical of formula (5c) or (5e) may be obtained by reacting a compound of formula 
wherein R, R32, R32xe2x80x2, A2, X, X1, (alk*) and m each have the above-given meaning, with a compound of formula
xe2x80x94X1xe2x80x2(O)Cxe2x80x94(oligomer)xe2x80x83xe2x80x83(9a),
wherein (oligomer) has the above-given meaning and X1xe2x80x2 is for example xe2x80x94OH or halogen, in particular chlorine, or together with xe2x80x94(O)Cxe2x80x94 forms an anhydride group, in a manner known per se.
The macromonomers of formula (4), wherein A is a direct bond and (oligomer) is a radical of formula (6cxe2x80x2) are known or may be prepared according to methods known in the art, for example as described in S. Kobayashi et al., Polymer Bulletin 13, p 447-451 (1985).
Likewise, the macromonomers of the formula 
wherein (alk*), Xxe2x80x2, X and (oligomer) each have the above-given meaning, may be obtained in a manner known per se, for example, by reacting a compound of formula 
wherein (alk*) has the above-given meaning, with a compound of the above-given formula (6), or by reacting a compound of formula 
with a compound of the above formula (9) wherein (alk*) and X1 each have the above-given meaning.
The compounds of the formula (8), (9), (9a), (10a), (10b), (12) and (12a) are known compounds which are commercially available or may be prepared according to known methods. For example, compounds of the formula (9) and (9a) wherein (oligomer) denotes a radical of formula (6a) may be prepared according to PCT application WO 92/09639 by copolymerizing one or more hydrophilic ethylenically unsaturated monomers in the presence of a functional chain transfer agent such as cysteamine hydrochloride, thioglycolic acid or the like.
The hydrophilic monomers or macromonomers may be applied to the initiator-modified primary polymer coating and polymerized there according to processes known per se. For example, the material comprising the primary polymer coating is immersed in a solution of the monomer or macromonomer, or a layer of monomer or macromonomer is first of all deposited on the modified material surface, for example, by dipping, spraying, spreading, knife coating, pouring, rolling, spin coating or vacuum vapor deposition. Suitable solvents, if used in the polymerization process, are, for example, water or dipolar aprotic solvents such as, for example, acetonitrile. The polymerization of the hydrophilic monomer or macromonomer on the material comprising the primary polymer coating then may be initiated, for example, thermally by the action of heat or preferably by irradiation, particularly by UV radiation. Suitable light sources for the irradiation are known to the artisan and comprise for example mercury lamps, high pressure mercury lamps, xenon lamps, carbon arc lamps or sunlight. The time period of irradiation may depend for example on the desired properties of the resulting composite material but is usually in the range of up to 30 minutes, preferably from 10 secondes to 10 minutes, and particularly preferably from 0.5 to 5 minutes. It is advantageous to carry out the irradiation in an atmosphere of inert gas. After the polymerization, any non-covalently bound monomers, polymers, oligomers or non-reacted macromonomers formed can be removed, for example by treatment with suitable solvents.
The coated material obtained according to the invention may be purified afterwards in a manner known per se, for example by washing or extraction with a suitable solvent such as water.
According to step (b) of the above-described coating process, the brushes of the primary coating obtained according to step (a) are provided with side chains by grafting a hydrophilic monomer or macromonomer onto the primary polymer coating. The final coating typically has a so-called bottle brush-type structure (BBT) composed of tethered xe2x80x9chairyxe2x80x9d chains. The BBT structure of the coatings of the invention may be varied within wide limits, for example by a suitable choice of reactive monomer, photoinitiator and chain length in step (a), or by a suitable choice of hydrophilic monomer or macromonomer and chain length in step (b). Such BBT structures in one embodiment comprise a long hydrophilic or hydrophobic backbone which carries relatively densely packed comparatively short hydrophilic side chains (called primary bottle brushes). Another embodiment relates to secondary bottle brushes which are characterized in that the hydrophilic side chains themselves carry densely packed hydrophilic xe2x80x9csecondaryxe2x80x9d side chains. Polymeric coatings of said primary and secondary BBT structures to a certain extent mimic highly water-retaining structures occurring in the human body, for example in cartilage or mucosal tissue.
The coating thickness of the macromonomers depends principally on the desired properties. It can be, for example, from 0.001 to 1000 xcexcm, preferably from 0.005 to 100 xcexcm, more preferably from 0.01 to 50 xcexcm, even more preferably from 0.01 to 5 xcexcm, especially preferably from 0.01 to 1 xcexcm and particularly preferably from 0.01 to 0.5 xcexcm.
A further embodiment of the invention relates to a material that is coated by the process of the invention.
The material that is coated by the process of the invention is, for example, an organic bulk material, preferably a biomedical device, e.g. an ophthalmic device, preferably a contact lens including both hard and particularly soft contact lenses, an intraocular lens or artificial cornea. Further examples are materials useful for example as wound healing dressings, eye bandages, materials for the sustained release of an active compound such as a drug delivery patch, moldings that can be used in surgery, such as heart valves, vascular grafts, catheters, artificial organs, encapsulated biologic implants, e.g. pancreatic islets, materials for prostheses such as bone substitutes, or moldings for diagnostics, membranes or biomedical instruments or apparatus.
The biomedical devices, e.g. ophthalmic devices obtained according to the invention have a variety of unexpected advantages over those of the prior art which make those devices very suitable for practical purposes,e.g. as contact lens for extended wear or intraocular lens. For example, they do have a high surface wettability which can be demonstrated by their contact angles, their water retention and their water-film break up time or tear film break up time (TBUT).
The TBUT plays an particularly important role in the field of ophthalmic devices such as contact lenses. Thus the facile movement of an eyelid over a contact lens has proven important for the comfort of the wearer; this sliding motion is fa cilitated by the presence of a continuous layer of tear fluid on the contact lens, a layer which lubricates the tissue/lens interface. However, clinical tests have shown that currently available contact lenses partially dry out between blinks, thus increasing friction between eyelid and the lens. The increased friction results in soreness of the eyes and reduced movement of the contact lenses. Now it has become feasible to considerably increase the TBUT of commercial contact lenses such as, for example, Focus Dailies(trademark), Focus New Vues(copyright) or Lotrafilcon A lenses, by applying a surface coating according to the invention. On the base curve of a contact lens, the pronounced lubricity of the coating facilitates the on-eye lens movement which is essential for extended wear of contact lenses. Moreover, the materials obtained by the process of the invention provide additional effects being essential for lenses for extended wear, such as an increased thickness of the pre-lens tear film which contributes substantially to low microbial adhesion and resistance to deposit formation. Due to the extremely soft and lubricious character of the novel surface coatings, biomedical articles such as in particular contact lenses coated by the process of the invention show a superior wearing comfort including improvements with respect to late day dryness and long term (overnight) wear. The novel surface coatings moreover interact in a reversible manner with occular mucus which contributes to the improved wearing comfort.
In addition, biomedical devices, e.g. ophthalmic devices such as contact lenses, coated by the process of the invention, have a very pronounced biocompatibility combined with good mechanical properties. For example, the devices are blood compatible and have a good tissue integration. In addition, there are generally no adverse eye effects observed, while the adsorption of proteins or lipids is low, also the salt deposit formation is lower than with conventional contact lenses. Generally, there is low fouling, low microbial adhesion and low bioerosion while good mechanical properties can be for example found in a low friction coefficient and low abrasion properties. Moreover, the dimensional stability of the materials obtained according to the invention is excellent. In addition, the attachment of a hydrophilic surface coating at a given bulk material according to the invention does not affect its visual transparency.
In summary, the ophthalmic devices obtained by the process of the invention, such as contact lenses and artificial comea, provide a combination of low spoilation with respect to cell debris, cosmetics, dust or dirt, solvent vapors or chemicals, with a high comfort for the patient wearing such opthalmic devices in view of the soft hydrogel surface which for example provides a very good on-eye movement of the ohthalmic device.
Biomedical devices such as renal dialysis membranes, blood storage bags, pacemaker leads or vascular grafts coated by the process of the invention resist fouling by proteins by virtue of the continuous layer of bound water, thus reducing the rate and extent of thrombosis. Blood-contacting devices fabricated according to the present invention are therefore haemocompatible and biocompatible.
In the examples, if not indicated otherwise, amounts are amounts by weight, temperatures are given in degrees Celsius. Tear break-up time values in general relate to the pre-lens tear film non-invasive break-up time (PLTF-NIBUT) that is determined following the procedure published by M. Guillon et al., Ophthal. Physiol. Opt. 9, 355-359 (1989) or M. Guillon et al., Optometry and Vision Science 74, 273-279 (1997). Average advancing and receding water contact angles of coated and non-coated lenses are determined with the dynamic Wilhelmy method using a Kruss K-12 instrument (Kruss GmbH, Hamburg, Germany). Wetting force on the solid is measured as the solid is immersed in or withdrawn from a liquid of known surface tension.
Surface Functionalization